Identification, Characterization, and Heritability of Murine Metastable Epialleles: Implications for Non-genetic Inheritance.

Generally repressed by epigenetic mechanisms, retrotransposons represent around 40% of the murine genome. At the Agouti viable yellow (Avy) locus, an endogenous retrovirus (ERV) of the intracisternal A particle (IAP) class retrotransposed upstream of the agouti coat-color locus, providing an alternative promoter that is variably DNA methylated in genetically identical individuals. This results in variable expressivity of coat color that is inherited transgenerationally. Here, a systematic genome-wide screen identifies multiple C57BL/6J murine IAPs with Avy epigenetic properties. Each exhibits a stable methylation state within an individual but varies between individuals. Only in rare instances do they act as promoters controlling adjacent gene expression. Their methylation state is locus-specific within an individual, and their flanking regions are enriched for CTCF. Variably methylated IAPs are reprogrammed after fertilization and re-established as variable loci in the next generation, indicating reconstruction of metastable epigenetic states and challenging the generalizability of non-genetic inheritance at these regions.

Structural basis of SARM1 activation, substrate recognition, and inhibition by small molecules.

The NADase SARM1 (sterile alpha and TIR motif containing 1) is a key executioner of axon degeneration and a therapeutic target for several neurodegenerative conditions. We show that a potent SARM1 inhibitor undergoes base exchange with the nicotinamide moiety of nicotinamide adenine dinucleotide (NAD+) to produce the bona fide inhibitor 1AD. We report structures of SARM1 in complex with 1AD, NAD+ mimetics and the allosteric activator nicotinamide mononucleotide (NMN). NMN binding triggers reorientation of the armadillo repeat (ARM) domains, which disrupts ARM:TIR interactions and leads to formation of a two-stranded TIR domain assembly. The active site spans two molecules in these assemblies, explaining the requirement of TIR domain self-association for NADase activity and axon degeneration. Our results reveal the mechanisms of SARM1 activation and substrate binding, providing rational avenues for the design of new therapeutics targeting SARM1.

VDX-111, a novel small molecule, induces necroptosis to inhibit ovarian cancer progression.

Epithelial ovarian cancers that are nonhomologous recombination deficient, as well as those that are recurrent and in a platinum-resistant state, have limited therapeutic options. The objectives of this study were to characterize the mechanism of action and investigate the therapeutic potential of a small molecule, VDX-111, against ovarian cancer. We examined the ability of VDX-111 to inhibit the growth of a panel of ovarian cancer cell lines, focusing on BRCA wild-type lines. We found that VDX-111 causes a dose-dependent loss of cell viability across ovarian cancer cell lines. Reverse phase protein array (RPPA) analysis was used to identify changes in cell signaling in response to VDX-111 treatment. An RPPA analysis performed on cells treated with VDX-111 detected changes in cell signaling related to autophagy and necroptosis. Immunoblots of OVCAR3 and SNU8 cells confirmed a dose-dependent increase in LC3A/B and RIPK1. Incucyte live cell imaging was used to measure cell proliferation and death in response to VDX-111 alone and with inhibitors of apoptosis, necroptosis, and autophagy. Annexin/PI assays suggested predominantly nonapoptotic cell death, while real-time kinetic imaging of cell growth indicated the necroptosis inhibitor, necrostatin-1, attenuates VDX-111-induced loss of cell viability, suggesting a necroptosis-dependent mechanism. Furthermore, VDX-111 inhibited tumor growth in patient-derived xenograft and syngeneic murine models. In conclusion, the cytotoxic effects of VDX-111 seen in vitro and in vivo appear to occur in a necroptosis-dependent manner and may promote an antitumor immune response.

Gender-inclusive language in midwifery and perinatal services: A guide and argument for justice.

Effective communication in relation to pregnancy and birth is crucial to quality care. A recent focus in reproductive healthcare on "sexed language" reflects an ideology of unchangeable sex binary and fear of erasure, from both cisgender women and the profession of midwifery. In this paper, we highlight how privileging sexed language causes harm to all who birth-including pregnant trans, gender diverse, and non-binary people-and is, therefore, unethical and incompatible with the principles of midwifery. We show how this argument, which conflates midwifery with essentialist thinking, is unstable, and perpetuates and misappropriates midwifery's marginalized status. We also explore how sex and gender essentialism can be understood as colonialist, heteropatriarchal, and universalist, and therefore, reinforcing of these harmful principles. Midwifery has both the opportunity and duty to uphold reproductive justice. Midwifery can be a leader in the decolonization of childbirth and in defending the rights of all childbearing people, the majority of whom are cisgender women. As the systemwide use of inclusive language is central to this commitment, we offer guidance in relation to how inclusive language in perinatal and midwifery services may be realized.

Concerns regarding health-related social media usage amongst otolaryngology patients.

PURPOSE: The objective of this study was to determine concerns of otolaryngology patients regarding health-related social media usage. METHODS: A total of 372 otolaryngology patients were asked to report their level of concern (on a scale of "not at all", "a little", "somewhat", or "highly" concerned) regarding health-related social media usage as it pertained to risk of "loss of privacy or anonymity related to your health condition", "reliability of disease/treatment information", and "reliability of physician reviews/recommendations". Demographics and social media usage patterns (on Facebook, Instagram, Twitter, TikTok or other platforms) were compared to concerns about health-related social media usage. RESULTS: The level of concern was highest for reliability of disease/treatment information and least for loss of privacy/anonymity (p < 0.001). Concern about loss of privacy/anonymity was associated with age over 25 years (OR = 3.12, 95%CI 1.66-5.86, p < 0.001) and negatively with daily use of Twitter (OR = 0.54, 95%CI 0.30-0.96, p = 0.035). Concern about reliability of disease/treatment information was negatively associated with Medicare insurance (OR = 0.57, 95%CI 0.35-0.93, p = 0.024), which is available to adults aged ≥65 years, and concern over reliability of physician reviews/recommendations was associated with patients identifying their race as Asian, American Indian and other (OR = 3.16, 95%CI 1.22-8.19, p = 0.018). CONCLUSIONS: The greatest concern about health-related social media usage is related to reliability of disease/treatment information, though notably less among patients with Medicare who represent adults of age 65 years or older. Concerns over loss of privacy/anonymity and reliability of physician reviews/recommendations are also prevalent and associated with patient demographics. These concerns may constrain utilization of social media for healthcare purposes, which highlights the importance of reliable sources of information.

Grief Coach: Feasibility and acceptability of a text message program for bereavement support among grievers in the United Kingdom.

To address gaps in bereavement services in the UK, a national charity offered free access to Grief Coach, a 12-month text message-based grief support program. To assess the feasibility and acceptability of the approach, this study examined program reach, retention, and user satisfaction. Over 4000 grievers enrolled in the program over 13.5 months; 6- and 12-month retention rates were 87.8% and 83.2%. Among individuals responding to a satisfaction survey (response rate = 55.9%), 94.8% rated the program as moderately or very helpful and 95.4% said it contributed to their sense of being supported in their grief. Common themes emerging from a qualitative analysis of the written comments were how the program helped with coping with the pain of grief and user appreciation of the program. Grief Coach may be a promising component of high-quality grief support to meet the needs of grieving people in the UK.

Niraparib and dostarlimab for the treatment of recurrent platinum-resistant ovarian cancer: results of a Phase II study (MOONSTONE/GOG-3032).

OBJECTIVE: This study assessed the efficacy, safety, and health-related quality of life (HRQoL) of the treatment regimen of dostarlimab, a programmed death-1 inhibitor, combined with niraparib, a poly (ADP-ribose) polymerase inhibitor, in patients with BRCA wild type (BRCAwt) recurrent platinum-resistant ovarian cancer (PROC) who had previously received bevacizumab treatment. METHODS: This Phase II, open-label, single-arm, multicenter study, conducted in the USA, enrolled patients with recurrent PROC to receive niraparib and dostarlimab until disease progression or unacceptable toxicity (up to 3 years). A preplanned interim futility analysis was performed after the first 41 patients had undergone ≥1 radiographic evaluation (approximately 9 weeks from the first treatment). RESULTS: The prespecified interim futility criterion was met and the study was therefore terminated. For the 41 patients assessed, the objective response rate (ORR) was 7.3% (95% confidence interval: 1.5-19.9); no patients achieved a complete response, 3 patients (7.3%) achieved a partial response (duration of response; 3.0, 3.8, and 9.2 months, respectively), and 9 patients (22.0%) had stable disease. In total, 39 patients (95.1%) experienced a treatment-related adverse event, but no new safety issues were observed. HRQoL, assessed using FOSI, or Functional Assessment of Cancer Therapy - Ovarian Symptom Index scores, worsened over time compared with baseline scores. CONCLUSIONS: The study was terminated due to the observed ORR at the interim futility analysis. This highlights a need for effective therapies in treating patients with recurrent BRCAwt PROC.

Unsupervised high-frequency smartphone-based cognitive assessments are reliable, valid, and feasible in older adults at risk for Alzheimer's disease.

OBJECTIVE: Smartphones have the potential for capturing subtle changes in cognition that characterize preclinical Alzheimer's disease (AD) in older adults. The Ambulatory Research in Cognition (ARC) smartphone application is based on principles from ecological momentary assessment (EMA) and administers brief tests of associative memory, processing speed, and working memory up to 4 times per day over 7 consecutive days. ARC was designed to be administered unsupervised using participants' personal devices in their everyday environments. METHODS: We evaluated the reliability and validity of ARC in a sample of 268 cognitively normal older adults (ages 65-97 years) and 22 individuals with very mild dementia (ages 61-88 years). Participants completed at least one 7-day cycle of ARC testing and conventional cognitive assessments; most also completed cerebrospinal fluid, amyloid and tau positron emission tomography, and structural magnetic resonance imaging studies. RESULTS: First, ARC tasks were reliable as between-person reliability across the 7-day cycle and test-retest reliabilities at 6-month and 1-year follow-ups all exceeded 0.85. Second, ARC demonstrated construct validity as evidenced by correlations with conventional cognitive measures (r = 0.53 between composite scores). Third, ARC measures correlated with AD biomarker burden at baseline to a similar degree as conventional cognitive measures. Finally, the intensive 7-day cycle indicated that ARC was feasible (86.50% approached chose to enroll), well tolerated (80.42% adherence, 4.83% dropout), and was rated favorably by older adult participants. CONCLUSIONS: Overall, the results suggest that ARC is reliable and valid and represents a feasible tool for assessing cognitive changes associated with the earliest stages of AD.

Effectiveness of the BNT162b2 (Pfizer-BioNTech) and the ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccines for reducing susceptibility to infection with the Delta variant (B.1.617.2) of SARS-CoV-2.

BACKGROUND: From January to May 2021 the alpha variant (B.1.1.7) of SARS-CoV-2 was the most commonly detected variant in the UK. Following this, the Delta variant (B.1.617.2) then became the predominant variant. The UK COVID-19 vaccination programme started on 8th December 2020. Prior to the Delta variant, most vaccine effectiveness studies focused on the alpha variant. We therefore aimed to estimate the effectiveness of the BNT162b2 (Pfizer-BioNTech) and the ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccines in preventing symptomatic and asymptomatic infection with respect to the Delta variant in a UK setting. METHODS: We used anonymised public health record data linked to infection data (PCR) using the Combined Intelligence for Population Health Action resource. We then constructed an SIR epidemic model to explain SARS-CoV-2 infection data across the Cheshire and Merseyside region of the UK. Vaccines were assumed to be effective after 21 days for 1 dose and 14 days for 2 doses. RESULTS: We determined that the effectiveness of the Oxford-AstraZeneca vaccine in reducing susceptibility to infection is 39% (95% credible interval [34, 43]) and 64% (95% credible interval [61, 67]) for a single dose and a double dose respectively. For the Pfizer-BioNTech vaccine, the effectiveness is 20% (95% credible interval [10, 28]) and 84% (95% credible interval [82, 86]) for a single-dose and a double dose respectively. CONCLUSION: Vaccine effectiveness for reducing susceptibility to SARS-CoV-2 infection shows noticeable improvement after receiving two doses of either vaccine. Findings also suggest that a full course of the Pfizer-BioNTech provides the optimal protection against infection with the Delta variant. This reinforces the need to complete the full course programme to maximise individual protection and reduce transmission.

Absolute Quantification of Nav1.5 Expression by Targeted Mass Spectrometry.

Nav1.5 is the pore forming α-subunit of the cardiac voltage-gated sodium channel that initiates cardiac action potential and regulates the human heartbeat. A normal level of Nav1.5 is crucial to cardiac function and health. Over- or under-expression of Nav1.5 can cause various cardiac diseases ranging from short PR intervals to Brugada syndromes. An assay that can directly quantify the protein amount in biological samples would be a priori to accurately diagnose and treat Nav1.5-associated cardiac diseases. Due to its large size (>200 KD), multipass transmembrane domains (24 transmembrane passes), and heavy modifications, Nav1.5 poses special quantitation challenges. To date, only the relative quantities of this protein have been measured in biological samples. Here, we describe the first targeted and mass spectrometry (MS)-based quantitative assay that can provide the copy numbers of Nav1.5 in cells with a well-defined lower limit of quantification (LLOQ) and precision. Applying the developed assay, we successfully quantified transiently expressed Nav1.5 in as few as 1.5 million Chinese hamster ovary (CHO) cells. The obtained quantity was 3 ± 2 fmol on the column and 3 ± 2 × 104 copies/cell. To our knowledge, this is the first absolute quantity of Nav1.5 measured in a biological sample.

The Lysozyme Inhibitor Thionine Acetate Is Also an Inhibitor of the Soluble Lytic Transglycosylase Slt35 from Escherichia coli.

Lytic transglycosylases such as Slt35 from E. coli are enzymes involved in bacterial cell wall remodelling and recycling, which represent potential targets for novel antibacterial agents. Here, we investigated a series of known glycosidase inhibitors for their ability to inhibit Slt35. While glycosidase inhibitors such as 1-deoxynojirimycin, castanospermine, thiamet G and miglitol had no effect, the phenothiazinium dye thionine acetate was found to be a weak inhibitor. IC50 values and binding constants for thionine acetate were similar for Slt35 and the hen egg white lysozyme. Molecular docking simulations suggest that thionine binds to the active site of both Slt35 and lysozyme, although it does not make direct interactions with the side-chain of the catalytic Asp and Glu residues as might be expected based on other inhibitors. Thionine acetate also increased the potency of the beta-lactam antibiotic ampicillin against a laboratory strain of E. coli.

The role of sex in the innate and adaptive immune environment of metastatic colorectal cancer.

BACKGROUND: Women with colorectal cancer (CRC) have a significant survival advantage over men. Sex influences on the tumour microenvironment (TME) are not well characterised, despite the importance of immune response in CRC. We hypothesised that sex-divergent immune responses could contribute to survival. METHODS: Using a murine model of metastatic CRC, we examined T cells, macrophages, and cytokines locally and systemically. TME and serum cytokines were measured by multiplex bead-based arrays, while FCA was used to identify cells and phenotypes. IHC provided spatial confirmation of T cell infiltration. RESULTS: Females had increased survival and T cell infiltration. CD8, CD4 and Th2 populations correlated with longer survival. Males had increased serum levels of chemokines and inflammation-associated cytokines. Within the TME, males had lower cytokine levels than females, and a shallower cytokine gradient to the periphery. Female tumours had elevated IL-10+ macrophages, which correlated with survival. CONCLUSIONS: These data demonstrate survival-associated differences in the immune response of males and females to metastatic CRC. Females showed changes in cytokine production accompanied by increased immune cell populations, biased toward Th2-axis phenotypes. Key differences in the immune response to CRC correlated with survival in this model. These differences support a multi-faceted shift across the TME.

The relationship between patient-centered care and outcomes in specialist drug and alcohol treatment: A systematic literature review.

Background: Patient-centered care is strongly advocated as a key for improving the quality of healthcare. Research examining the impact of patient-centered care in healthcare has concluded that there are demonstrable albeit inconsistent relationships between patient experience, quality of care, and healthcare outcomes. Knowledge of the impact of patient-centered care in the treatment of substance use disorder is limited. The aim of this review was to assess relationships between indicators of patient-centered care (satisfaction and patient-reported experience measures) and patient outcomes (substance use, psychological wellbeing, and service use) among people attending treatment for substance use disorder. Methods: A systematic electronic literature search of a range of databases was conducted with variations of the search terms 'patient-centered care', 'substance use disorders', and residential or community specialist 'treatment'. The populations, interventions and outcomes were summarized and described according to the PRISMA statement. Results: A total of 25 articles were identified, of which only five included a patient-centered indicator other than satisfaction. Indicators of patient-centered care showed a generally positive association with improved outcomes, particularly between satisfaction with treatment and substance use. Nonetheless, mixed and contradictory results were not uncommon, more so for psychological wellbeing outcomes. Conclusions: There were demonstrable relationships between patient-centered indicators and outcomes for people receiving treatment for substance use disorder. However, conclusions are limited due to underrepresentation of patient-reported experience measures. Further research in the area is needed involving comparisons of patient centered indicators with outcomes and use of patient-reported experience measures together with satisfaction. Registration number: CRD42018092829.

Age-Related Differences in Motivational Integration and Cognitive Control.

Motivational incentives play an influential role in value-based decision-making and cognitive control. A compelling hypothesis in the literature suggests that the motivational value of diverse incentives are integrated in the brain into a common currency value signal that influences decision-making and behavior. To investigate whether motivational integration processes change during healthy aging, we tested older (N = 44) and younger (N = 54) adults in an innovative incentive integration task paradigm that establishes dissociable and additive effects of liquid (e.g., juice, neutral, saltwater) and monetary incentives on cognitive task performance. The results reveal that motivational incentives improve cognitive task performance in both older and younger adults, providing novel evidence demonstrating that age-related cognitive control deficits can be ameliorated with sufficient incentive motivation. Additional analyses revealed clear age-related differences in motivational integration. Younger adult task performance was modulated by both monetary and liquid incentives, whereas monetary reward effects were more gradual in older adults and more strongly impacted by trial-by-trial performance feedback. A surprising discovery was that older adults shifted attention from liquid valence toward monetary reward throughout task performance, but younger adults shifted attention from monetary reward toward integrating both monetary reward and liquid valence by the end of the task, suggesting differential strategic utilization of incentives. These data suggest that older adults may have impairments in incentive integration and employ different motivational strategies to improve cognitive task performance. The findings suggest potential candidate neural mechanisms that may serve as the locus of age-related change, providing targets for future cognitive neuroscience investigations.

Inhaled corticosteroid prescribing in a pediatric emergency department: Sustained success and prescription filling rates.

OBJECTIVE: To determine if improvement in Inhaled Corticosteroid (ICS) prescribing in the pediatric emergency department (PED) can be sustained after transition from intense intervention to low-intervention phase, and to determine ICS fill rates. METHODS: A Quality Improvement (QI) project began in Aug 2012. Results through Feb 2014 were previously published. In Feb 2014 interventions were scaled back to determine the sustainability of QI success. Eligible patients included children aged 2-17 seen in the PED for asthma between Feb 2014 and Sept 2016. The primary change when moving to the low-intervention phase was stopping monthly attending feedback. The primary outcome was the proportion of patients who were prescribed an ICS at the time of PED discharge. The secondary objective of this study was to determine the proportion of patients who filled their ICS prescription in the 6 months following Emergency Department (ED) visit. RESULTS: The goal rate of ICS prescribing was 75%. After transition to the low-intervention phase, the ICS prescribing rate was maintained at a median of 79% through Sept 2016. ICS fill rate in the first 30 days following ED visit was 89%, although this quickly fell to below 40% for months 2-6. CONCLUSIONS: The ICS prescribing rate remained the goal of 75% over a 2.5-year period after transition to a low-intervention phase. High ICS fill rates immediately after ED visit have been demonstrated. However, rapid decline in these rates over subsequent months suggests a need for future efforts to focus on long-term ICS adherence among children with ED visits for asthma.

Review of mental health promotion interventions in schools.

PURPOSE: The prevalence of mental disorders amongst children and adolescents is an increasing global problem. Schools have been positioned at the forefront of promoting positive mental health and well-being through implementing evidence-based interventions. The aim of this paper is to review current evidence-based research of mental health promotion interventions in schools and examine the reported effectiveness to identify those interventions that can support current policy and ensure that limited resources are appropriately used. METHODS: The authors reviewed the current state of knowledge on school mental health promotion interventions globally. Two major databases, SCOPUS and ERIC were utilised to capture the social science, health, arts and humanities, and education literature. RESULTS: Initial searches identified 25 articles reporting on mental health promotion interventions in schools. When mapped against the inclusion and exclusion criteria, 10 studies were included and explored. Three of these were qualitative and seven were quantitative. CONCLUSIONS: A range of interventions have been tested for mental health promotion in schools in the last decade with variable degrees of success. Our review demonstrates that there is still a need for a stronger and broader evidence base in the field of mental health promotion, which should focus on both universal work and targeted approaches to fully address mental health in our young populations.

Helmet use in bicycles and non-motorised wheeled recreational vehicles in children.

AIM: Injuries involving non-motorised wheeled recreational vehicles (NMWRV) and bicycles are a common cause for hospitalisation in children. Studies show that helmet use whilst bicycle riding can decrease mortality and morbidity due to head injury. However, there remains an important proportion of children who are non-helmet users (NHU). This study aims to investigate helmet use and attitudes and injury patterns in children presenting with trauma after riding bicycles and other NMWRVs. METHODS: A prospective cohort study was undertaken over 8 months of children aged 0-16 years, who presented with injury secondary to bicycle or NMWRV to the emergency department of two tertiary paediatric centres. Demographics, incident, injury severity and attitudes towards helmet use were compared between helmet users and NHU. RESULTS: A total of 342 children were included - 41% (n = 139) scooter riders, 39% (n = 133) bicyclists, 18% (n = 61) skateboarders and 2% (n = 9) in-line skaters. Of those interviewed (n = 161), 58% (n = 93) wore a helmet, with children riding bicycles significantly more likely to be helmeted than NMWRV (75 vs. 48%, P = 0.01). NHU were more likely to be admitted to hospital (P = 0.05) and to sustain a major head injury (P = 0.009). The main influence on helmet use was parental rules. The biggest factor influencing non-helmet use was perceived low levels of danger. CONCLUSIONS: Despite legislation mandating this, helmet use is not universal in cyclists, particularly younger riders. Even fewer NMWRV riders use them. To promote helmet use, a multifaceted approach aimed at altering community norms and individual behaviours and attitudes is required.

Reclassification of the Specialized Metabolite Producer Pseudomonas mesoacidophila ATCC 31433 as a Member of the Burkholderia cepacia Complex.

Pseudomonas mesoacidophila ATCC 31433 is a Gram-negative bacterium, first isolated from Japanese soil samples, that produces the monobactam isosulfazecin and the ß-lactam-potentiating bulgecins. To characterize the biosynthetic potential of P. mesoacidophila ATCC 31433, its complete genome was determined using single-molecule real-time DNA sequence analysis. The 7.8-Mb genome comprised four replicons, three chromosomal (each encoding rRNA) and one plasmid. Phylogenetic analysis demonstrated that P. mesoacidophila ATCC 31433 was misclassified at the time of its deposition and is a member of the Burkholderia cepacia complex, most closely related to Burkholderia ubonensis The sequenced genome shows considerable additional biosynthetic potential; known gene clusters for malleilactone, ornibactin, isosulfazecin, alkylhydroxyquinoline, and pyrrolnitrin biosynthesis and several uncharacterized biosynthetic gene clusters for polyketides, nonribosomal peptides, and other metabolites were identified. Furthermore, P. mesoacidophila ATCC 31433 harbors many genes associated with environmental resilience and antibiotic resistance and was resistant to a range of antibiotics and metal ions. In summary, this bioactive strain should be designated B. cepacia complex strain ATCC 31433, pending further detailed taxonomic characterization.IMPORTANCE This work reports the complete genome sequence of Pseudomonas mesoacidophila ATCC 31433, a known producer of bioactive compounds. Large numbers of both known and novel biosynthetic gene clusters were identified, indicating that P. mesoacidophila ATCC 31433 is an untapped resource for discovery of novel bioactive compounds. Phylogenetic analysis demonstrated that P. mesoacidophila ATCC 31433 is in fact a member of the Burkholderia cepacia complex, most closely related to the species Burkholderia ubonensis Further investigation of the classification and biosynthetic potential of P. mesoacidophila ATCC 31433 is warranted.

Altered Prefrontal Excitation/Inhibition Balance and Prefrontal Output: Markers of Aging in Human Memory Networks.

Memory impairments and heightened prefrontal cortical (PFC) activity are hallmarks of cognitive and neurobiological human aging. While structural integrity of PFC gray matter and interregional white matter tracts are thought to impact memory processing, the balance of neurotransmitters within the PFC itself is less well understood. We used fMRI to establish whole-brain networks involved in a memory encoding task and dynamic causal models (DCMs) for fMRI to determine the causal relationships between these areas. These data revealed enhanced connectivity from PFC to medial temporal cortex that negatively correlated with recall ability. To better understand the intrinsic activity within the PFC, DCM for EEG was employed after continuous theta burst transcranial magnetic stimulation (TMS) to the PFC to assess the effect on excitatory/inhibitory (E/I) synaptic ratios and behavior. These data revealed that the young cohort had a stable E/I ratio that was unaffected by the TMS intervention, while the aged cohort exhibited lower E/I ratios driven by a greater intrinsic inhibitory tone. TMS to the aged cohort resulted in decreased intrinsic inhibition and a decrement in memory performance. These results demonstrate increased top-down influence of PFC upon medial temporal lobe in healthy aging that is associated with decreased memory and may be due to unstable local inhibitory tone within the PFC.